Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-?-lactamase-1.

ABSTRACT: The efficacy of ?-lactam antibiotics is threatened by the emergence and global spread of metallo-?-lactamase (MBL) mediated resistance, specifically New Delhi metallo-?-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related ?-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.

SUBMITTER: Chen AY 

PROVIDER: S-EPMC5599375 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature